2-47403201-C-T

Variant names:

• chr2-47403201-C-T
• rs878853797
• NM_000251.3:c.10C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000251.3(MSH2):​c.10C>T​(p.Gln4*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000692 in 1,444,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q4Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 6.99

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 1423 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47403201-C-T is Pathogenic according to our data. Variant chr2-47403201-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 578361.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.10C>T	p.Gln4*	stop_gained	Exon 1 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.10C>T	p.Gln4*	stop_gained	Exon 1 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444196 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 716882

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33274

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 41868

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25736

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39078

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 83514

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 50468

Gnomad4 NFE exome AF: 9.05e-7 AC: 1 AN: 1104904

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 59754

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Oct 15, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 1 of the MSH2 gene, creating a premature translation stop signal. However this variant may escape nonsense-mediated mRNA decay due to secondary initiation at one of multiple downstream AUG start codons. Experimental studies have shown that a protein with a deletion of 25 amino acids of the N-terminal domain has been observed as partially functional (PMID: 21837758). An alternative MSH2 transcript (NM_001258281) lacking the first 66 amino acids of the primary transcript, is expressed at similar or higher levels in human tissues (https://gnomad.broadinstitute.org/). Premature stop codons located in close proximity to the canonical Met1 start codon often show a decrease in nonsense-mediated mRNA decay efficiency (PMID: 27618451). Missense variants impacting the start codon at Met1 are classified as VUS (ClinVar Variation ID: 90832, 90833, 230889). This variant has been identified in a cohort of individuals affected with esophageal squamous cell carcinoma (PMID: 31396961). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). The clinical impact of truncations in MSH2 prior to a secondary in-frame methionine at amino acid residue 26 is not fully understood at this time. Until further functional and clinical evidence is obtained, based on the evidence available this variant is classified as Likely Pathogenic. -

Jul 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q4* variant (also known as c.10C>T), located in coding exon 1 of the MSH2 gene, results from a C to T substitution at nucleotide position 10. This changes the amino acid from a glutamine to a stop codon within coding exon 1. The predicted stop codon occurs within the first 150 nucleotides of the MSH2 gene. This alteration may escape nonsense-mediated mRNA decay and/or be rescued by re-initiation through use of a downstream, in-frame AUG at codon 26 (Farrington SM et al. Am J Hum Genet, 1998 Sep;63:749-59; Kets CM et al. Eur J Hum Genet, 2009 Feb;17:159-64; Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). The exact functional effect of this alteration is unknown; however, MutS alpha complexes formed using recombinantly expressed wild type MSH6 and MSH2 with a deletion of the first 25 amino acids of the protein, demonstrated partially retained function in several biochemical assays that measured ATP binding, ATPase activity, mismatch binding, and sliding clamp formation (Cyr JL et al. Mol Carcinog, 2012 Aug;51:647-58). This alteration has been identified in multiple individuals diagnosed with breast cancer (Sun J et al. Clin. Cancer Res., 2017 Oct;23:6113-6119; Hu L et al. NPJ Breast Cancer, 2022 Apr;8:52). This variant was also identified in 1/2121 samples from a cohort of Chinese patients diagnosed with esophageal squamous cell carcinoma (Ko JM et al. Int J Cancer, 2020 02;146:1042-1051). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Lynch syndrome 1 Pathogenic:1

Jul 26, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

not specified Uncertain:1

Feb 24, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH2 c.10C>T (p.Gln4X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The next downstream in-frame ATG start site is at codon 26. Other truncating variants downstream of the c.10C>T nonsense variant but upstream of the potential new start codon have been classified as pathogenic in our laboratory, ClinVar, and HGMD. However, studies in patients with start-loss variants and functional studies involving a truncated Msh2 variant lacking the first 25 amino acids suggest that Msh2 proteins utilizing an alternative downstream start codon retain functional, albeit reduced, activity (e.g., Farrington_1998, Kets_2009, Cyr_2012). The variant was absent in 218968 control chromosomes. c.10C>T has been reported in the literature in individuals affected with breast cancer and esophageal squamous cell carcinoma, however without strong evidence for causality (e.g., Sun_2017, Ko_2020, Hu_2022). These reports therefore do not provide conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact of the variant on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln4*) in the MSH2 gene. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 26 has the potential to rescue this variant. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer and/or esophageal cancer (PMID: 28724667, 31396961, 35449176). ClinVar contains an entry for this variant (Variation ID: 578361). Reports on variants that affect the MSH2 initiator codon, c.1A>C and c.1A>T, indicate that Met26 may serve as an alternate initiator codon (PMID: 21837758, 9718327, 18781192). An experimental study of a recombinant MSH2 protein lacking the first 25 amino acid residues has shown that the truncated protein remains partially functional (PMID: 21837758). The clinical significance of these findings is unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.76
GERP RS		5.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs878853797; hg19: chr2-47630340; COSMIC: COSV51878319;